The present invention relates to an apparatus for the in-vivo non-invasive measurement of a biological parameter concerning a bodily fluid of a person or animal, wherein the apparatus is provided with at least two pairs of electrodes to be placed on the skin of a part of the body, a pair of input electrodes for feeding a measuring alternating current to the part of the body and a measuring pair of electrodes for measuring the voltage at the electrodes of the measuring pair of electrodes, comprising a current source providing the measuring alternating current, a converter for the transformation of the measuring voltage into a bio-impedance signal, being a measure of the bio-impedance of the part of the body, and means for the generation of signals which form a measure for further variables with the aid of which said parameter can be determined using the calculating model, said signals encompassing a signal forming a measure for the time derivative of the bio-impedance signal.
Such an apparatus is known from the international patent application WO-A-90/00367. This known apparatus is used to determine a number of biological parameters of the thorax of a patient by means of a bio-impedance measurement. However, the measurement is rather inaccurate because the fluid distribution in the patient is not taken into account. With the known apparatus there is also a local bio-impedance measurement; this is used for the determination of an average arterial pressure.
It is the object of the invention to apply the measuring results becoming available when employing this apparatus in such a way that the biological parameter can be determined more accurately.
To this end the apparatus of the invention is characterized in that the current source or current sources have an electrically symmetrical configuration and is provided with a galvanic separation in relation to the instrument earth and is suitable for generating a measuring current having a constant amplitude on at least two frequencies, a low frequency and a high frequency, in a frequency range of up to about 2000 kHz. This provides independent measurements and reduces interfering effects caused by electromagnetic radiation at high frequencies. It is noted that galvanic separation of the current sources is in itself known in the art; see for instance the article in Med. and Biol. Engineering and Computing, Vol. 28 (1990), January, No. 1, entitled: xe2x80x9cTwo-frequency impedance plethysmograph: real and imaginary partsxe2x80x9d. FIG. 2a of this application shows galvanic separation of the current sources and the measuring part of the instrument. The configuration employs thereto, however, three separate transformers to which large stray capacities attach which are detrimental for the accuracy of the instrument.
The biological parameters that can be determined by means of the apparatus according to the invention include preferably the measuring of a circulatory parameter and more preferably the stroke volume of a heart. Further, the so-called cardiac output which is derived from the stroke volume and the heart rhythm, the so-called cardiac index, the left ventricle ejection time, the right ventricle ejection time, the preejection period, the Heather index, the acceleration index, and venous occlusion plethysmography can also be determined by means of the apparatus. These terms are known to the expert and need no further explanation. Other biological parameters that may be determined by means of the apparatus are, for instance, the distribution between extracellular and intracellular bodily fluids and the distribution of fluid during a septic shock.
It is observed that the application of several frequencies for the determination of a biological parameter is known as such.
In the article xe2x80x9cMultiple frequency system for body composition measurementxe2x80x9d, Proc. of the Int. Conf. of the IEEE Engineering in Medicine and Biology Society, Vol. 15, October 1993, pp. 1020, 1021, currents of different frequencies are used for the measurement and determination of a body parameter. The maximum frequency is, however, only 100 kHz, and no measures are given for combatting radiation problems. The publication is limited to the determination of changes in the bladder contents.
The article xe2x80x9cTwo-frequency impedance plethysmograph: real and imaginary partsxe2x80x9d, Med. and Biol. Engineering and Computing, 28 (1990) January, No. 1, pp. 38-42, describes a multi-frequency measuring system for the analysis of fluid volume ratios in the thorax where two different frequencies are used having a maximum measuring frequency of only 110 kHz.
The article xe2x80x9cMicroprocessor-based system for measurement of electrical impedance during haemodialysis and in postoperative carexe2x80x9d, Med. and Biol. Engineering and Computing, 26 (1988) January, No. 1, pp. 75-80, describes a system for tetrapolar impedance plethysmography for the determination of fluid and the fluid volume ratios in the thorax. Three oscillators are used for this purpose, two of which operate on 2xc2xd and 100 kHz respectively and a third has an oscillation frequency of 1 kHz to 1 MHz.
The U.S. Pat. No. 4,870,578 describes an apparatus for the determination of the stroke volume of a heart by means of bio-impedance measurement. The apparatus according to this publication comprises means for sending a constant, high frequency current through the thorax of a person to be examined, as well as means for measuring a consequentially induced voltage over the thorax, from which signal the impedance of the particular thorax is derived. From this impedance the time derivative is determined, and a limited time portion of this time derivative subsequently serves as a measure for the stroke volume of the heart in the thorax.
U.S. Pat. No. 5,309,917 discusses a further development of such a bio-impedance measuring system departing from the known methods of determination according to Kubicek and Sramek.
According to Kubicek the stroke volume of the heart is determined by the formula   SV  =      ρ    ⁢          xe2x80x83        ⁢                  L        2                    Z        0        2              ⁢                            (                                    ⅆ              Z                                      ⅆ              T                                )                min            ·      VET      
In this formula xcfx81 is the specific resistance of the blood, L is the distance at which the electrodes are placed for measuring the voltage, Z0 is the average thorax resistance and VET is the ventricular ejection time. The current source provides a current having a frequency of about 100 kHz.
An alternative form according to which the stroke volume is determined is provided by Sramek:   SV  =                    V        EPT                    Z        0              ·                  (                  VET          ⁢                      (                                          ⅆ                Z                                            ⅆ                t                                      )                          )            min      
in which VEPT is the volume of the thorax participating in the electric conduction. This volume depends on the height and weight of the particular person.
The general formula for the stroke volume may be expressed as   SV  =            μ      ·      η        ⁢          xe2x80x83        ⁢                            (                      VET            ⁢                          (                                                ⅆ                  Z                                                  ⅆ                  t                                            )                                )                min                    Z        0            
in which xcex7 is a personal form factor, and xcexc a corrective factor for oedema formation in the thorax.
According to U.S. Pat. No. 5,309,917 a time frequency diagram is determined for the measured time derivative of the bio-impedance signal. The stroke volume of the heart is then derived from this frequency diagram, while the stroke volume is assumed to be dependent on the time lapse between the first frequency signal in this distribution and the point in time when the time derivative of the bio-impedance signal reaches the maximum value.
Optimal separation of measurement results becoming available on the two different frequencies is obtained because the low frequency fl is in the region of about 1-64 kHz and the high frequency fh in the region of about 32-2000 kHz, such that in all cases fl is smaller than fh. By choosing the measurement frequencies thus, the difference in sensitivity is optimal for both situations. The relatively low frequency currents are transmitted mainly through the extracellular fluid, while the high frequency currents are also transmitted through the intracellular fluid. Fluid distribution may, for instance, by analyzed by means of the so-called Cole-Cole-model, which is based on a Nyquist analysis of a simple equivalent-circuit diagram of the thorax, based on a parallel circuit of a purely resistive component for the relatively low frequencies and for the high frequencies a series connection of a resistive and a capacitive component. Consequently, by applying the known formulas for the determination of the stroke volume and other biological parameters, different frequencies provide independent measurements for those parameters. These measurements provide information about the above-mentioned correction factor xcexc. With the aid of the measured impedance Z0, or through determination of the measured phase angle, "psgr", the ratio intracellular and extracellular fluid can be determined at different frequencies.
Preferably the current source is suitable for simultaneous generation of the two frequencies. This has the advantage that the time the patient has to be connected to the apparatus for measurement is shortened.
In addition it is desirable that means are provided for the determination of maximum phase shift between the measuring current and the measuring voltage as a function of the frequency. This allows the electric transfer function of the particular part of the body to be determined, with the angular frequency being the independent variable. This permits at the same time the determination of the ratio between intracellular and extracellular fluid; because this ratio is directly related to the frequency at which the phase angle is at a maximum. With healthy test persons this maximum phase angle is at about 9 to 10xc2x0 at 70 kHz. This corresponds to an intracellular/extracellular fluid ratio of 3:7. With septic patients the maximum phase angle is, for instance, between 3 and 6 xc2x0.
A preferred embodiment of the apparatus according to the invention is characterized in that said apparatus comprises four pairs of electrodes, two pairs of electrodes being intended for taking a transversal bio-impedance measurement and two pairs of electrodes being intended for taking a local bio-impedance measurement. In the case that the measurement is carried out on the thorax, the local bio-impedance measurement is to be carried out at a location removed from the heart.
The term xe2x80x9ctransversal measuringxe2x80x9d used above, indicates a measurement in which the current runs substantially lengthways of the person to be examined.
The measure discussed just now allows a further correction to be carried out on the resulting measurements, due to the different test results of the cardiovascular system at a relatively low and a relatively high frequency. With a local bio-impedance measurement a measurement check is thus obtained in which the interfering influence of the cardiovascular system is eliminated. In this way the local measurement produces a correction signal to compensate the transversal measurement.
The apparatus is preferably provided with connecting means for connecting the current source and the transformer in series, in order to sequentially carry out the local bio-impedance measurement and the transversal bio-impedance measurement. This limits the number of components comprising the apparatus, and by always employing the same system parts an optimally reproducible measurement is obtained.
In another embodiment the apparatus according to the invention is characterized in that said apparatus comprises a current source or current sources suitable for the simultaneous generation of signals at two low frequencies and two high frequencies, so as to limit the inconvenience for a patient to be examined. These frequencies all range from about 4 to 2000 kHz, with a first low frequency and a first high frequency being coupled to a first two pairs of electrodes to carry out the local bio-impedance measurement and the second low frequency and the second high frequency being coupled to the second two pairs of electrodes to carry out the transversal bio-impedance measurement. In this way, both measurements can be carried out simultaneously.
It is further desirable that the measurement amplifier or measurement amplifiers are configured electrically symmetrical and are provided with a galvanic separation in relation to ground. This increases the resistance to common mode interference signals.
Also, the input stage of the apparatus is inductively coupled, thereby reducing transmission of the interference signal residue.